Stroke, resulting in acute loss of sensorimotor function. is a main cause of disability in modem society. Yet, most individuals following sensorimotor stroke show a certain, albeit variable, degree of functional recovery over time. This restoration of function is commonly thought to be associated with brain plasticity, however, the exact relationship between recovery of function and brain plasticity, and its underlying mechanism, remain unknown. The proposed project is aimed at improving our understanding of the neurophysiological mechanisms that underlie functional recovery after stroke. Our preliminary data suggest that recovery of sensorimotor function is associated with biphasic spatio-temporal alterations in brain activation patterns. These and other data suggest the hypotheses that hnctional recovery after stroke is mediated initially by rapid unmashng of existing contralesional neuronal circuitry subserving sensorimotor function, followed at later stages by ipsilesional neuroanatomical and vascular remodeling, whch may be enhanced by specific pharmacological treatment with i) a neurotrophic growth factor and/or ii) vascular endothelial growth factor (VEGF). To test these hypotheses we will perform animal studies in which the functional MRI methods developed during previous cycles of this grant (CBF, CBV, BOLD, CMR(02)) will be employed to assess neuronal activity, in relation to sensorimotor function as measured with various behavioral tests. These data will be correlated with physiological, structural and molecular changes as determined from parallel MRI, electrophysiology, autoradiography and immunohistochemistry studies. Finally, in pilot treatment studies we will assess the effects of pharmacological therapy with i) a neurotrophic growth factor and ii) VEGF on functional recovery and cerebral reorganization. The above studies will provide new and detailed information on the pattern of functional field shifts after stroke, its underlying neurophysiological and neuroanatomical basis, and, importantly, its relationshp with functional recovery. Moreover, the treatment studies will shed light on the clinical potentials of growth factor therapy after stroke, and the role of advanced MRI methods to critically evaluate mechanisms of recovery, which could contribute to the development and optimization of neurorehabilitative approaches to improve stroke recovery.